Carbon Monoxide Improves Cardiac Function and Mitochondrial Population Quality in a Mouse Model of Metabolic Syndrome 英文参考文献.docVIP

Carbon Monoxide Improves Cardiac Function and Mitochondrial Population Quality in a Mouse Model of Metabolic Syndrome 英文参考文献.doc

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Carbon Monoxide Improves Cardiac Function and Mitochondrial Population Quality in a Mouse Model of Metabolic Syndrome 英文参考文献

CarbonMonoxideImprovesCardiacFunctionand MitochondrialPopulationQualityinaMouseModelof MetabolicSyndrome SteveLancel1*,DavidMontaigne1,XavierMarechal1,CamilleMarciniak1,SidiMohamedHassoun1, BrigitteDecoster1,CarolineBallot1,CarolineBlazejewski1,DelphineCorseaux2,BernadetteLescure3, RobertoMotterlini4,RemiNeviere1 1EA4484,PhysiologyDepartment,Lille2University,Lille,France,2EA2693,Lille2University,Lille,France,3INSERMIFR65,InstitutdeRechercheenSanteSaintAntoine (Irssa),FacultyofMedicine,Paris,France,4INSERMU955,FacultyofMedicine,Paris-EstUniversity,Cre′teil,France Abstract Aims:Metabolicsyndromeinducescardiacdysfunctionassociatedwithmitochondriaabnormalities.Aslowlevelsofcarbon monoxide(CO)mayimprovemyocardialandmitochondrialactivities,wetestedwhetheraCO-releasingmolecule(CORM-3) reverses metabolic syndrome-induced cardiac alteration through changes in mitochondrial biogenesis, dynamics and autophagy. MethodsandResults:Micewerefedwithnormaldiet(ND)orhigh-fatdiet(HFD)fortwelveweeks.Then,micereceivedtwo intraperitonealinjectionsofCORM-3(10mg.kg21),withthesecondonegiven16hoursafterthefirst.Contractilefunctionin isolatedheartsandmitochondrialparameterswereevaluated24hoursafterthelastinjection.Mitochondrialpopulationwas explored by electron microscopy. Changes in mitochondrial dynamics, biogenesis and autophagy were assessed by western-blotandRT-qPCR.LeftventriculardevelopedpressurewasreducedinHFDhearts.MitochondriafromHFDhearts presented reduced membrane potential and diminished ADP-coupled respiration. CORM-3 restored both cardiac and mitochondrialfunctions.SizeandnumberofmitochondriaincreasedintheHFDheartsbutnotintheCORM-3–treatedHFD group. CORM-3 modulated HFD-activated mitochondrial fusion and biogenesis signalling. While autophagy was not activatedintheHFDgroup,CORM-3increasedtheautophagymarkerLC3-II.Finally,exvivoexperimentsdemonstratedthat autophagyinhibitionby3-methyladenineabolishedthecardioprotectiveeffectsofCORM-3. Conclusion: CORM-3 may modulate pathways con

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